Standard Bioequivalence Criteria Research Articles

A randomized, double blind, single dose, comparative study of the pharmacokinetics, safety and immunogenicity of MB02 (bevacizumab biosimilar) and reference bevacizumab in healthy male volunteers

AimsThe pharmacokinetic (PK) similarity between MB02, a proposed bevacizumab biosimilar, and reference bevacizumab approved from the USA (US‐bevacizumab) and European Union (EU‐bevacizumab) was evaluated. Safety and immunogenicity were also assessed.MethodsIn this phase 1, randomized, double blind, single dose, parallel group study, 114 healthy male volunteers were randomized 1:1:1 to receive a 3 mg/kg intravenous dose of MB02, US‐bevacizumab or EU‐bevacizumab, and evaluated for 100 days. PK similarity between MB02 and reference bevacizumab was determined using the standard bioequivalence criteria (0.80–1.25) for the area under the serum concentration–time curve from time 0 extrapolated to infinity (AUC(0‐∞)) and the maximum observed serum concentration (Cmax).ResultsBaseline demographics were similar across treatment groups. All study drugs exhibited similar PK profile. The 90% confidence interval for the geometric lead square means ratios for the primary parameters AUC(0‐∞) and Cmax for MB02, US‐bevacizumab and EU‐bevacizumab were fully contained within the pre‐defined bioequivalence limits for the 3 pairwise comparisons: AUC(0‐∞) (MB02:US‐bevacizumab 0.998 [0.944 to 1.05]; MB02:EU‐bevacizumab 1.07 [1.00 to 1.14]; and US‐bevacizumab:EU‐bevacizumab 0.934 [0.884 to 0.988]) and Cmax (MB02:US‐bevacizumab 0.983 [0.897 to 1.08]; MB02:EU‐bevacizumab 1.06 [0.976 to 1.16]; and; US‐bevacizumab: EU‐bevacizumab 0.926 [0.851 to 1.01]). Treatment emergent adverse events were reported in 87 subjects (76.3%), most being mild and with comparable incidence among treatment groups. Thirty‐three subjects (28.9%) reported 56 possibly related treatment emergent adverse events with comparable incidence across treatments, the most frequent being headache (10.5%) and fatigue (3.5%). Anti‐drug antibody incidence was low and similar between treatment groups.ConclusionsThis study demonstrates the PK similarity and bioequivalence of MB02 to the reference bevacizumab, whether approved from USA or EU. The safety and immunogenicity profile of MB02 was shown also to be similar to the bevacizumab reference product (NCT 04238663).

Model-Based Elaboration of a Limited Sampling Strategy in the Bioequivalence Assessment of Highly Variable Dabigatran

Background: The bioequivalence (BE) assessment of generic (Test) and brand name (Reference) formulations of drugs with steep exposure-response relationships exhibiting high pharmacokinetic (PK) variability such as dabigatran represent an expensive challenge for pharmaceutical companies. Supported by the population pharmacokinetics (pop-PK) approach, the present article investigates modelling potential to assess BE using a reduced number of blood samples. Methods: Pop-PK models for the Reference and Test formulations were developed retrospectively using standard modeling techniques for a BE study of dabigatran. Reduced sampling scenarios were selected and the developed pop- PK models were refitted on each dataset for the respective formulations. These models were simulated to generate virtual PK profiles to be tested with the standard BE criteria, in order to identify the scenarios maintaining the original BE conclusions with the least samples required. Results: The BE study original data was best described as a pop-PK model presenting two compartments with first order elimination and absorption, as well as an absorption lag time. Sex was identified as a significant covariate with impact on bioavailability. Using a rational sampling selection procedure under the framework of modeling and simulation, the results proved that the BE verdict could be maintained with only five of the 20 original blood samples using the current regulatory BE standards and criteria. Conclusion: We conclude that the pop-PK model-based BE assessment can be an efficient tool for aiding the BE assessment of dabigatran by significantly reducing the number of samples required, and consequently lower trial costs and increase benefits for enrolled participants.

Pharmacokinetics and Pharmacodynamics of Twice Daily and Once Daily Regimens of Empagliflozin in Healthy Subjects

PurposeThis study was undertaken to compare the steady-state pharmacokinetic and pharmacodynamic properties of empagliflozin 5 mg twice daily (BID) and 10 mg once daily (QD) in healthy subjects. MethodsIn an open-label, 2-way crossover study, subjects (n = 16) received empagliflozin 5 mg BID for 5 days and empagliflozin 10 mg QD for 5 days in a randomized order, with a washout period of ≥6 days between each treatment. The primary objective was the comparison of the overall exposure during a 24-hour period at steady state (AUC0−24,ss) for empagliflozin, based on standard bioequivalence criteria, with BID and QD dose regimens. FindingsThe study population comprised 7 (43.8%) men and 9 (56.3%) women with a baseline median age of 38.0 years (range, 23−47 years) and a median body mass index of 23.3 kg/m2 (range, 19.8−27.8 kg/m2). Based on standard bioequivalence criteria, there was no difference in the overall exposure of empagliflozin between BID and QD dose regimens (geometric mean ratio of AUC0−24,ss for empagliflozin 5 mg BID compared with empagliflozin 10 mg QD = 99.36%; 90% CI, 94.29−104.71). For empagliflozin 10 mg QD, mean (%CV) AUC during the dosing interval was 1900 nmol · h/L (20.6%), mean (%CV) Cmax,ss was 330 nmol/L (25.3%), and median (range) Tmax,ss was 1.0 hour (0.7−2.0 hours). For empagliflozin 5 mg BID, mean (%CV) AUC during the dosing interval was 1010 nmol · h/L (15.1%) and 867 nmol · h/L (18.6%) after the morning and evening dose, respectively, mean (%CV) Cmax,ss was 193 nmol/L (16.5%) and 120 nmol/L (21.0%), respectively, and median Tmax,ss was 1.0 hour (range, 0.7−2.0 hours) and 2.0 hours (range, 1.0−4.0 hours), respectively. The mean (%CV) cumulative amount of glucose excreted in urine during 24 hours was 52.1 g (32.1%) with empagliflozin 5 mg BID and 43.9 g (30.3%) with empagliflozin 10 mg QD. Adverse events were reported in six subjects (37.5%) receiving empagliflozin 5 mg BID and four (25.0%) receiving empagliflozin 10 mg QD. Headache was the most frequent AE. No severe, serious, or drug-related AEs were reported. ImplicationsThere were no clinically relevant differences in pharmacokinetic or pharmacodynamic properties between BID and QD dose regimens of empagliflozin in healthy subjects. Both dose regimens were well tolerated. EU Clinical Trials Register (EudraCT) number: 2009-012524-90.

Assessing Pharmacokinetic Interactions Between the Sodium Glucose Cotransporter 2 Inhibitor Empagliflozin and Hydrochlorothiazide or Torasemide in Patients With Type 2 Diabetes Mellitus: A Randomized, Open-Label, Crossover Study

PurposeEmpagliflozin is a potent, selective sodium glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus. Thiazide or loop diuretics are commonly prescribed in patients with type 2 diabetes mellitus. This study investigated potential pharmacokinetic drug−drug interactions between empagliflozin and hydrochlorothiazide (HCTZ) or torasemide (TOR). MethodsThis was an open-label, crossover study. Patients with type 2 diabetes mellitus were randomized to receive empagliflozin 25 mg once daily for 5 days and either HCTZ 25 mg once daily for 4 days followed by HCTZ 25 mg once daily plus empagliflozin 25 mg once daily for 5 days or TOR 5 mg once daily for 4 days followed by TOR 5 mg once daily plus empagliflozin once daily for 5 days in 1 of 4 sequences, with at least a 7-day washout period between treatments. Pharmacokinetic parameters of empagliflozin, HCTZ, and TOR were assessed and standard bioequivalence criteria (80%−125%) were applied. Tolerability assessments included the frequency of adverse events and an investigator assessment of global tolerability. FindingsMean (SD) age of the 22 patients treated was 54.0 (8.1) years and body mass index was 27.1 (3.7) kg/m2. Coadministration of empagliflozin with HCTZ or TOR had no effect on exposure to empagliflozin, HCTZ, or TOR. Geometric mean ratios (90% CIs) for empagliflozin AUC over a uniform dosing interval and Cmax at steady state were 107.1% (90% CI, 97.1−118.1) and 102.8% (90% CI, 88.6−119.3), respectively, when coadministered with HCTZ versus administration alone, and 107.8% (90% CI, 100.1−116.1) and 107.5% (90% CI, 97.9−118.0), respectively, when coadministered with TOR versus administration alone. For HCTZ, the geometric mean ratios for AUC over a uniform dosing interval and Cmax at steady state were 96.3% (90% CI, 89.1−104.0) and 101.8% (90% CI, 88.6−116.9), respectively, and for TOR were 101.4% (90% CI, 99.1−103.9) and 104.4% (90% CI, 93.8−116.3), respectively, for combined treatment versus administration alone. The pharmacokinetic profiles of empagliflozin, HCTZ, and TOR were similar after administration alone and in combination. Global tolerability was good for all patients after each treatment, and no severe or serious adverse events were reported. ImplicationsNo pharmacokinetic drug−drug interaction was observed between empagliflozin and HCTZ or TOR. ClinicalTrials.gov identifier: NCT01276288.

Prograf Five Milligrams Versus Tacrolimus Medis in Healthy Volunteers: A Bioequivalence Study

For FDA approval, bioequivalence of a generic version of Tacrolimus must be demonstrated in a randomized, two-treatments, two-periods, two-sequences, single-dose crossover study in healthy adult volunteers. Currently there are at least 3 differents generic equivalent for Tacrolimus, that are approved by the EMA and the FDA, with a USA market share of nearly 50%. However, the market share of generic immunosuppressive drugs in the Middle East region is still very low due to the reluctance of the physician to accept Tacrolimus generics, considered to be a narrow therapeutic window drug, that are approved using the standard bioequivalence criteria of 80% to 125%. Herein we present a bioequivalence study of a new Tacrolimus generic, Tacrolimus Medis 5 mg developed by Medis Tunisia batch number 12G3003 compared with Prograf® 5 mg batch number 7202 manufactured by Astellas Toyama Co., Ltd. Japan and HIKMA Pharmaceuticals, Amman-Jordan in healthy adult volunteers using the 90%–111% criteria recommended for drugs with narrow therapeutic window. The study was, balanced, randomized, two-treatments, two-periods, two-sequences, single dose, crossover, comparative oral bioavailability study in healthy adult human volunteers. The study was carried out in accordance with the Basic Principles defined in the U.S. 21 CFR Part 312.20, the principles enunciated in the Declaration of Helsinki (World Medical Association Declaration of Helsinki). Thirty six non-smoking healthy, as determined by medical history, volunteers, 18 years and older, were included. Following randomization using a computer software (pharma solution) the volunteers were given a single oral dose of 5 milligrams following a 12 hour fast with a wash out period of 7 days. Pharmacokinetics profile with blood levels at: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours were performed following each dose. Tacrolimus plasma level was determined using an HPLC validated method (Transmedical For Life S.A.R.L. Beirut Lebanon), for accuracy, suitability, reproducibility, precision , long-term stability and robustness. Physical examinations, hematology, urine analysis and serum chemistry tests were performed at screening and before dosing in each period and at end of the study. Volunteers were monitored for safety and adverse events throughout the study. Both products were bioequivalent at the entire pharmacokinetic parameters tested. The LSM were 95.31%–101.21% for AUC, 94.65%–101.11% for AUC0-inf, 97.15%–100.02% for Cmax and 91.54%–103.75% for Half-life. Respectively all of which are within the EU and FDA approval limits (90–111%) indicating that the 2 products are equivalent and switchable.

Effect of Empagliflozin on the Steady-State Pharmacokinetics of Ethinylestradiol and Levonorgestrel in Healthy Female Volunteers

Empagliflozin is a potent, selective inhibitor of sodium glucose cotransporter 2 in development for the treatment of patients with type 2 diabetes mellitus. Oral contraceptives may be co-administered with antidiabetic agents over long periods of time, therefore potential drug-drug interactions between oral contraceptives and antidiabetic drugs should be investigated. The effect of multiple oral doses of empagliflozin 25 mg once daily (qd) on the steady-state pharmacokinetics of the combined oral contraceptive ethinylestradiol (EE) 30 μg/levonorgestrel (LNG) 150 μg qd was investigated. This was a phase I, open-label, two-period, fixed sequence study. The study was performed at the Human Pharmacology Centre/Department of Translational Medicine, Boehringer Ingelheim, Biberach, Germany. Eighteen healthy premenopausal women participated in the study. There was a mandatory run-in period in which participants received EE 30 μg/LNG 150 μg qd for 21-48 days followed by a treatment-free interval of 7 days. Participants then received EE 30 μg/LNG 150 μg qd for 14 days (reference; period 1), followed by EE 30 μg/LNG 150 μg qd plus empagliflozin 25 mg qd for 7 days (test; period 2). The pharmacokinetics of EE and LNG at steady state based on the primary endpoints of area under the steady-state plasma concentration-time curve during a dosage interval τ (AUC(τ,ss)) and maximum steady-state plasma concentration during a dosage interval (C (max,ss)) were the main outcome measures. The pharmacokinetics of EE and LNG were not affected by co-administration with empagliflozin. Geometric mean ratios (90 % CI) of AUC(τ,ss) and C (max,ss) for EE were 102.82 % (97.58, 108.35) and 99.22 % (93.40, 105.39), respectively. For LNG, these values were 101.94 % (98.54, 105.47) and 105.81 % (99.47, 112.55), respectively. The 90 % CIs were within the standard bioequivalence boundaries of 80-125 %. There were no relevant changes in the time to reach peak levels (t (max,ss)) or terminal elimination half-life (t (½,ss)) of EE and LNG between test and reference treatments. Ten women in each treatment had at least one adverse event (AE). Severe AEs were reported by three women in the reference period and one woman in the test period. There were no serious AEs or premature discontinuations. The combination of EE 30 μg/LNG 150 μg and empagliflozin 25 mg was well tolerated. Based on standard bioequivalence criteria, empagliflozin had no effect on the pharmacokinetics of EE and LNG, indicating that no dose adjustment of EE 30 μg/LNG 150 μg is required when empagliflozin is co-administered.

Effects of Multiple Doses of Albiglutide on the Pharmacokinetics, Pharmacodynamics, and Safety of Digoxin, Warfarin, or a Low-Dose Oral Contraceptive

Aims: Albiglutide is a glucagon–like peptide–1 analog that is currently under investigation for the treatment of type 2 diabetes mellitus as a once–weekly injection. Three open–label phase 1 studies were conducted in healthy human participants to investigate potential pharmacokinetic (PK) and/or pharmacodynamic (PD) interactions between albiglutide and medications that may be used concomitantly. Methods: Digoxin 0.5 mg, warfarin 25 mg, or a standard, low–dose oral contraceptive containing norethindrone (NE) 0.5 mg and ethinyl estradiol (EE) 0.035 mg were administered alone and after steady–state albiglutide exposure (50 mg weekly for 4–5 weeks). The lack of a drug–drug interaction was concluded if the 90% CIs of geometric least–squares means ratio of area under the curve and maximum concentration were fully contained within 0.80 to 1.25. The effects of albiglutide on the PD of warfarin (international normalized ratio) and on the PD of a low–dose oral contraceptive (luteinizing hormone [LH], follicle–stimulating hormone [FSH], and progesterone) were assessed. Safety and tolerability were also assessed. Results: Overall, the PK profiles of digoxin, warfarin, NE, and EE were unaffected by albiglutide administration; standard bioequivalence criteria were met with a few exceptions that were not considered clinically relevant. Warfarin international normalized ratio was unaffected by albiglutide administration. No clinically meaningful differences in LH, FSH, or progesterone were observed. Most treatment–emergent adverse events were mild, and all resolved by study end. Conclusion: Based on tolerability and the lack of clinically significant PK or PD interactions, no dose adjustments should be required when albiglutide is administered concomitantly with these medications.

Evaluation of Bioequivalence and Cardio-Hepatic Safety of a Single Dose of Fixed Dose Combination of Artemether and Lumefantrine

Background and objective: The existing fixed-dose combination, Coartem® (artemether 20 mg and lumefantrine 80 mg) requires 4 tablets per dose and a total of 24 tablets for the six-dose regimen for the treatment of uncomplicated P. falciparum malaria compromising the patient compliance. Also, the cardiotoxicity due to lumefantrine because of its structural similarity with halofantrine remains a matter of debate in therapeutics. To enhance the patient compliance, the fixed-dose combination of artemether/lumefantrine (80/480 mg) is formulated by Sequel Pharmachem Pvt. Ltd. India. In the present study, this fixed dose combination (test product) was evaluated for its bioequivalence to the reference product, Coartem® 20/120 mg (artemether 20 mg and lumefantrine 120 mg) of Novartis Pharma Ltd. with assessment of cardio-hepatic safety. Methods: A randomized, open label, two-treatment, two-period, two-sequence, single-dose, crossover bioequivalence study with comparative safety evaluation was conducted on 72 healthy Indian human subjects under a fed condition. Quantification of artemether, dihydroartemisinin, and lumefantrine was done by a validated LC-MS/ MS method. For bioequivalence, AUC0-240, AUC0-inf and Cmax for artemether and lumefantrine were considered. Safety assessment was done by monitoring vital signs, QTc interval, serum ALT and AST values before and after treatment. Max QTc, baseline-corrected QTcmax, AST and ALT values were considered for statistical comparison between the two treatments. Drug plasma concentrations estimated at identical time points with the ECG recordings were correlated with ECG parameters. Results: The test product was bioequivalent to the reference product as per the standard bioequivalence criteria. There was no clinically significant difference between the two treatments for all the safety parameters. No significant observation suggestive of cardiotoxicity and hepatotoxicity was noted in this study. Conclusion: The test product can be used as a therapeutic option with likely better patient compliance in the treatment of uncomplicated P. falciparum malaria.

Xyntha® is effective and safe in previously treated patients with severe haemophilia A: Final results of a pivotal phase III study

Background: Xyntha® (albumin‐free cell culture process) is a BDDrFVIII manufactured using an albumin‐free cell culture process and purified using a chemically synthesized peptide affinity ligand instead of a murine monoclonal antibody. A virus‐retaining filtration step has been included as an additional safety precaution during manufacture. The potency assignment of Xyntha® has been aligned to the one‐stage clotting assay, to permit routine clinical monitoring, as for other rFVIII products, without specialized standards.Objectives: The primary objectives were to demonstrate inhibitor safety for Xyntha® and to demonstrate pharmacokinetic (PK) equivalence of Xyntha® with Advate® by standard bioequivalence criteria using the one‐stage assay. Other objectives included characterizing the PK of Xyntha® over time, and to determine efficacy of Xyntha® for prevention and treatment of bleeding episodes. Adverse events and consumption over time in patients treated with Xyntha® were also assessed.Methods: PK profiles of Xyntha® and Advate® were assessed in a randomized double‐blind crossover fashion, in 30 previously treated patients (PTPs) (≥12 years; FVIII:C ≤1%) using the standard bioequivalence approach based upon the one‐stage clotting assay. Safety and efficacy of Xyntha® were also assessed in 94 PTPs (FVIII:C ≤2%), which included the PK subjects, during 6 months of open label routine prophylaxis supplemented with on‐demand treatment as necessary. A follow‐up PK assessment with Xyntha® was performed in PK subjects after 6 months.Summary: Two patients had transient, low‐titre, clinically silent inhibitors (0.98 BU mL−1 and 1.21 BU mL−1), each detected by routine surveillance on a single occasion (both with negative follow‐up testing); this rate met prespecified safety goals. Corresponding ELISAs for FVIII antibodies were negative for both patients. No patient had a positive ELISA immune response to CHO cell protein or to the peptide affinity ligand used for Xyntha® purification. Pharmacokinetic equivalence of Xyntha® and Advate® was demonstrated (n = 30). Ratios of geometric least‐square means for K‐value, AUCt, AUC∞ were 100%, 89.8% and 88.0%, respectively, and associated 90% confidence intervals were within the bioequivalence window of 80–125%. Twenty‐five subjects had a baseline and 6 month follow‐up PK assessment with Xyntha®. Mean K‐value and t1/2 for Xyntha® were 2.23 (±0.39) IU dL−1 per IU kg−1 and 11.8 (±5.1) hours, respectively at baseline and the 6 month follow‐up PK profile was unchanged. Eighty‐nine of 94 patients accrued at least 50 Xyntha® exposure days. Median routine prophylaxis dose was 30.2 IU kg−1. During routine prophylaxis, the median annualized bleed rate was 1.9 (mean 3.9, range 0–42.1), and 43 of 94 (45.7%) patients experienced no bleeding episodes. One hundred and eighty‐seven bleeding episodes were treated on‐demand with a median dose of 30.6 IU kg−1 and 92.5% resolved with one or two infusions. The overall adverse event (AE) profile was consistent with the AE profile of ReFacto and other rFVIII products.Conclusions: Inhibitor safety results show no evidence of neoantigenicity and the AE profile demonstrates safety in PTPs with haemophilia A. Xyntha® is pharmacokinetically equivalent to Advate® based on one‐stage FVIII activity assessments, and Xyntha® PK is stable over 6 months of use. The product is effective in the prevention and treatment of bleeding episodes.

Influence of food on the pharmacokinetics of apricitabine, a novel deoxycytidine analogue reverse transcriptase inhibitor

Objective: Apricitabine is a novel deoxycytidine analogue reverse transcriptase inhibitor with clinical efficacy against both wild-type and drug-resistant HIV. The objective of this study was to evaluate the influence of feeding on apricitabine absorption and plasma pharmacokinetics. Research design/methods: Twenty healthy, male, HIV-negative volunteers were recruited for this randomised, open-label, crossover study and administered 1200 mg apricitabine orally either following fasting or a high-fat meal. Multiple blood samples were collected over a time course between 0 and 36 h following dosing, and plasma apricitabine concentration was measured using liquid chromatography–tandem mass spectrometry. Main outcome measures: Pharmacokinetic parameters were calculated from the drug concentration–time data for apricitabine using noncompartmental methods. Geometric means for maximum concentration (Cmax) and area under the apricitabine concentration versus time curve (AUC) for both the fasted and fed states were calculated and tested for bioequivalence at the 0.05 level by constructing the 90% confidence interval for the ratio of geometric means. Results: Apricitabine was well tolerated by all study participants. Plasma concentrations increased rapidly following oral administration, with Cmax being attained within 2 – 4 h. The pharmacokinetics of apricitabine was similar between the two states: the geometric means of both Cmax and AUC increased slightly between fasting and the administration of a high-fat meal, however the 90% confidence intervals around the ratio of the geometric means were within the standard bioequivalence criteria. Conclusion: Bioequivalence between the fed and fasting states was identified, indicating that a high-fat meal had no significant impact on the pharmacokinetics of single 1200 mg doses of apricitabine in healthy volunteers.

P4-406: Tarenflurbil (MPC-7869), a selective Aβ42-lowering agent, has no significant effect on drugs metabolized by CYP2C9

Alzheimer's disease is the most common type of dementia among the elderly. Its histopathologic features include phosphorylated Tau neurofibrillary tangles and amyloid beta senile plaques. In randomized, double-blind Phase II studies, the Selective Aβ42-Lowering Agent (SALA) tarenflurbil (MPC-7869) has demonstrated efficacy and tolerability. In earlier studies, CYP2C9 inhibition was demonstrated in vitro. Therefore, tarenflurbil has the potential to inhibit CYP2C9 in vivo. Sixteen healthy subjects participated in this third-party blind, placebo-controlled, randomized, crossover, Phase I study. Participants received either placebo or two 400-mg oral tablets of tarenflurbil every 12 hours for 9 consecutive days. On Day 6, each subject received one 500-mg oral tablet of tolbutamide, a CYP2C9 probe substrate. After the 14-day washout period, the treatments were switched (ie, subjects received the other treatment). Blood samples were collected throughout the study. Blood and urine samples were obtained on Day 6, prior to the morning dose of tarenflurbil or placebo and tolbutamide, and throughout the 96 hours after tolbutamide administration. The 90% confidence intervals for tolbutamide AUC(0–∞) (110%–120%) and Cmax (88%–112%) were within the standard bioequivalence criteria (80%–125%). Five days after administration of tarenflurbil 800 mg BID, the difference between mean tolbutamide exposure AUC(0–∞) with and without tarenflurbil was less than 15%. Furthermore, the formation clearance of 4-hydroxytolbutamide was similar for the treated and untreated states. Tarenflurbil has low potential for inhibition-based metabolic drug-drug interactions. Because of its amyloid-lowering properties, tarenflurbil holds promise as a disease-modifying agent for Alzheimer's disease.

What is the true risk of a pharmacokinetic drug–drug interaction?

Reports on pharmacokinetic drug–drug interaction studies account for a major fraction of manuscripts in clinical pharmacology journals; this issue of European Journal of Clinical Pharmacology contains three of them [1–3]. Most of the published reports are positive, i.e. they show some degree of change in the pharmacokinetics of drug A when drug B is co-administered. A standard conclusion of such results is that great care should be applied if the two drugs are given concomitantly. In contrast, many patients take five or more different drugs every day [4], often because there is a clear therapeutic indication for each of them, and nobody really cares about interactions as such, but rather a general clinical monitoring of adverse events and therapeutic effects is done. Indeed, this turns out to be sufficient for patient safety in most cases. However, if in clinical studies a pronounced pharmacokinetic interaction between two partners has been reported, such as the effect of gemfibrozil on cerivastatin [5] or that of mibefradil on CYP3A4 substrates [6], this is also often disregarded by clinicians, and these two cases even required market withdrawal of the drugs. How may we estimate true risk of a drug–drug interaction and identify those interactions that are clinically important in order to generate a signal which clinicians can rely on? Of course, the most reliable data would come from prospective, randomised, double-blind clinical trials using clinical endpoints, but this approach is not feasible for the multitude of potential interactions. We therefore rely on pharmacokinetics and/or on pharmacodynamics of drug A. This is justified because most interactions on the pharmacokinetic level will just change the intensity of the effect and will not qualitatively change therapy, although there may be exceptions in the case of an altered formation of active metabolites and/or a different tissue distribution. How much of a pharmacokinetic change should then be considered as relevant? The definition of bioequivalence, which is considered as the basis for interchangeability of two preparations, has been strictly formalized in respective guidelines [7–10] and usually requires that two preparations differ in mean area under curve (AUC) and Cmax values by not more than 0.8to 1.25-fold. Interchangeability is also the question in the case of pharmacokinetic drug–drug interactions: The clinician needs to know whether the concentrations and related effects of drug A are the same with and without concomitant administration of drug B, or whether some adjustment of the treatment or dosage is needed. Accordingly, it has been proposed to handle drug– drug interactions as an equivalence problem [11]. From a statistical point of view, this is very reasonable because it addresses power limitations and the validity of negative results, and there are also tools to assess interindividual variation in the degree of change (“individual bioavailability” methods) [8, 10]. In contrast to bioequivalence, however, the margins defining that a treatment with co-medication is not interchangeable to the treatment without co-medication are less clear. To be on the safe side, the same strict limits as applied for bioequivalence assessment have been proposed, and fulfilling the standard bioequivalence criteria usually means that a drug–drug interaction is not clinically relevant. However, even in regulatory guidelines, it is acknowledged that depending on the drug, different “no effect boundaries” may be appropriate [12, 13]. The criteria for the assessment of bioequivalence and of drug–drug interactions differ because Eur J Clin Pharmacol (2007) 63:897–899 DOI 10.1007/s00228-007-0357-6

Selegiline Transdermal System: An Examination of the Potential for CYP450‐Dependent Pharmacokinetic Interactions With 3 Psychotropic Medications

Selegiline transdermal system (STS) is a recently approved monoamine oxidase inhibitor antidepressant. This article reports results from 3 studies examining the potential for cytochrome P450-dependent pharmacokinetic interactions between STS and 3 psychotropic medications that might be coadministered. Three open-label, randomized, Latin square, 3-sequence crossover design studies were conducted with healthy volunteers to determine the pharmacokinetic parameters of STS 6 mg/24 h and test drug (alprazolam, olanzapine, or risperidone) when administered alone and concomitantly. All pharmacokinetic parameters of interest were unaltered following selegiline or test drug monotherapy when compared to concomitant therapy. This was confirmed by least squares mean ratios and their 90% confidence intervals of log(e)-transformed C(max) and AUC(tau) values, using either standard bioequivalence criteria of 80% to 125% or study-defined 70% to 143% boundary criteria. These results demonstrate that STS 6 mg/24 h may provide an antidepressant option that is unlikely to result in CYP450-mediated pharmacokinetic drug-drug interactions.

A pharmacokinetic and clinical review of the potential clinical impact of using different formulations of cyclosporin A

A meeting of 14 transplant and pharmacokinetic specialists from Europe and North America was convened in November 2001 to evaluate scientific and clinical data regarding the use of different formulations of cyclosporin A (CsA). The following consensus was achieved. (1) CsA is a critical-dose drug with a narrow therapeutic window. Clinical outcomes after transplantation are affected by the pharmacokinetic properties of CsA, particularly by its bioavailability, and by intrapatient variability in CsA exposure. (2) Standard bioequivalence criteria do not address differences in CsA pharmacokinetics between transplant recipients and healthy volunteers, or between subpopulations of transplant recipients. (3) In some circumstances, currently available formulations of CsA that meet standard bioequivalence criteria are likely to be nonequivalent with respect to pharmacokinetic characteristics. (4) The choice of CsA formulation can affect the short- and long-term clinical outcome. Currently, there is a lack of clinical comparisons between generic CsA formulations and the Neoral® formulation (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey). Initial retrospective data from the Collaborative Transplant Study suggest that use of generic CsA formulations may result in reduced graft survival at 1 year. (5) Management of transplant recipients by monitoring Neoral concentrations 2 hours after dosing (C 2) reduces the incidence and severity of acute rejection compared with monitoring of trough concentrations with no increase in toxicity. C 2 monitoring has been developed based on the pharmacokinetics of Neoral only and has not been evaluated or validated for generic formulations of CsA. (6) The major costs of care after transplantation relate to the management of poor clinical outcomes and toxicity. CsA formulations with different pharmacokinetic properties may be associated with varying clinical outcomes, which would be expected to affect total health care costs. (7) The transplant physician is responsible for selecting immunosuppressive agents and formulations for his or her patients. Any switch between CsA formulations in a particular patient should take place only in a controlled setting with adequate pharmacokinetic monitoring.